Muscle-relaxing tranquilizer compositions



United States Patent MUS'CLE-RELAXIN G TRAN QUILIZER COMPOSITIONS Jay Morton Beiler, Whitemarsh, Robert R. Brendel, Oreland, and Gustav J. Martin, Philadelphia, Pa., assignors to The National Drug Company, Philadelphia, Pa., a corporation of Delaware No Drawing. Application February 2, 1955 Serial No. 485,806

3 Claims. (Cl. 167-65) combinations of (1) the pharmacologically active benzyl-' acetamideswith (2) the pharmacologically active dioxolanes, dithiolanes and a-glyceryl ethers.

The benzylacetamides used in these compositions are preferably those having the formula:

oH-pnooN X R R,

wherein n is an integer from 0 to 7; X is a member of the group consisting of hydrogen, halogen, lower alkyl (e. g., methyl) and lower alkoxy (e. g., methoxy); R is a member of the group consisting of alkyl, cycloalkyl, alkenyl and cycloalkenyl; and R and R are each members of the group consisting of hydrogen, lower alkyl and allyl. Preferred are those compounds wherein R is allyl, especially allylbenzylacetamide. Other such compounds include allyl alpha phenylethylacetamide, allyl p methoxybenzylacetamide, allyl p chlorobenzylacetamide, allyl m xylylacetamide, allyl 0 xylylacetamide, isopropyl alpha phenylethylacetamide, n amyl alpha phenylethylacetamide, isobutyl alpha phenylethylacetamide, N,N diallylallylbenzylacetamide, N,N diallylallyl alpha phenylethylacetamide, N,N diallyl A cyclopentenylbenzylacetamide, N,N diallylbenzylcyclopentylacetamide and diethylallylbenzylacetamide. The benzylacetamides may be prepared by any desired procedure. One such general procedure is described in copending application Serial No. 398,428, now abandoned, another publication which discloses the preparation of the acetamides used in this invention is the article by Micucci et al., Exp. Med. Surg. 11, 185-191 (1935).

As to the second component, the preferred members are the 2,2 dialkyl 4 hydroxymethyl 1,3 dioxolanes, particularly, those in which the alkyl groups in the 2-position are lower alkyl and contain a total of 6 to 10 carbon l atoms, especially 2,2 diisopropyl 4 hydroxymethyl 1,3 dioxolane (Dimethylane). Other useful 2,2-dilower alkyl-4-hydroxymethyl-1,3-dioxolanes include those in which the 2,2-di-lower alkyl substituents are methyl, ethyl; methyl propyl; methyl isopropyl; methyl amyl; ethyl hexyl; methyl cyclohexyl; ethyl propyl; ethyl isopropyl; ethyl hexyl, methyl nonyl, ethyl nonyl, methyl heptyl, etc. Pharmacologically active dioxolanes, such as 2 methyl 2 (1' hydroxymethylamyl) 1,3 dioxolane may also be used. In addition, the pharmacologically active a-glyceryl esters, particularly o-toloxy-1,2-propanediol, may be employed as the second component.

It has now been found that the combination of pharmacologically active dioxolanes, dithiolanes (or glyceryl ethers) with benzylacetamides gives an enhanced muscle relaxant eifect entirely unexpected from a consideration of the effects obtained using these components separately.

To illustrate this effect, tests have been made and duration paralysis (duration determined by re-establishment of the righting reflex) recorded, with mice used as the test animals. In these tests it was found that, although 400 mg./k. orally of dioxolane resulted in a duration paralysis of about 35 minutes and 200 mg./k. of allylbenzylacetamide gave sedation but no hypnosis, the simultaneous administration of the two medicinals resulted in a muscle relaxant effect lasting over two hours. In a further test, it was found that although administration of 500 mg./k. dioxolane and 400 mg./k. allylbenzylacetamide gave duration paralysis times of about 45 minutes and 76 minutes respectively, the concurrent administration of the two yielded an effect lasting over five hours. The tests, therefore, clearly illustrate that the addition of a benzylacetamide to a dioxolane-type or a-glyceryl ether-type muscle relaxant results in marked potentiation of the relaxant effect. 7

For administration, the compositions of the invention may be prepared in any of the well-known dosage-unit forms. Thus, the compositions may be prepared for administration in tablets, capsules, suspensions, elixirs, etc.

Of these forms, it is preferred to administer the compositions of the invention in capsules, especially in the form of gelatin capsules externally coated with an acidinsoluble, alkali-soluble coating. This coating may take the form of a cellulose-containing ester or ether containing free carboxyl groups, such as those prepared by condensing incompletely esterified or etherified cellulose (e. g. cellulose acetate, cellulose propionate, cellulose acetate butyrate, ethyl or butyl cellulose containing free hydroxyl groups) with polycarboxylic acids (e. g. phthalic or maleic acids or, preferably, their anhydrides or acid halides). Such capsules are especially desirable since, due to their acid-insoluble coating, they do not disintegrate until they have passed through the stomach and into the intestines. A simple method for preparing capsules consists of dissolving the desired amount of benzylacetamide (e. g. 25 g. allylbenzylacetamide) in the desired amount of dioxolane (e. g. g. dimethylane) with the aid of heat, then filling soft gelatin capsules with 250 mg. portions of the mixture. The resulting product may then be enteric-coated by standard procedure, if desired.

For the preparation of tablets the usual procedures may be followed. Thus, the mixture of active ingredients may be compounded to contain fillers and/or binders, such as starch, dextrose, stearates, carbonates, kaolin or talc, then compressed to form the tablets. The elixirs and suspensions may also be prepared by dissolving or suspending in alcoholic or aqueous media. Such liquid containing forms may obviously include flavoring materials and other desirable additives. A typical suspension may be prepared as follows:

Dissolve .6 ml. each of .1% aqueous methyl, propyl and butyl p-hydroxybenzoate in 50 ml. glycerine with the application of heat and agitation. In a separate container, triturate .6 g. tragacanth with 10 ml. glycerine and add g. magnesium aluminum silicate to the triturated mixture, then add the glycerine solution of p-hydroxybenzoates to the tragacanth mixture and stir until uniformity is attained. To the resulting composition, add, with stirring, a solution of 2 g. allylbenzylacetamide in 8 g. Dimethylane. Add, to the resulting mixture, suflicient 70% aqueous solution of d-sorbitol, to attain a total volume of 600 ml. and homogenize the resulting composition for use.

Compositions may also be prepared for subcutaneous use by dissolving the mixture of active ingredients then using the resulting solutions for injection.

The various dosage usage forms may be prepared to contain any desired quantity of active ingredients. In

ordinary usage, a quantity of approximately 500 mgm. .of the acetamide and from about 500 mgm. to 2000 mgm. of the dioxolane (or a-glyceryl ether) are needed daily. Thus, the various dosage unit forms may be compounded in tablets or capsules to contain about 50 to 100 mgm.- of acetamide and about 50 to 200 mgm. of dioxolane. Larger or smaller quantities of the active ingredients may, of course, be utilized. Elixirs and suspensions are preferably prepared to contain about 2 mg. of active ingredients per ml. of liquid.

This invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A composition comprising (1) hypnotic benzylacetamides of the formula:

(CHDHH Rt HOHC 0 N X I l R2 wherein n is an integer from 0 to 7; X is a member of the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is a member of the group consisting of alkyl, cycloalkyl, alkenyl and cycloalkenyl; and R and R are each members of the group consisting of hydrogen, lower alkyl and allyl, and (2) a member of the group consisting of relaxant 1,3-dioxolanes, dithiolanes, and alpha glyceryl ethers, the ratio of benzylacetamide to the relaxant being approximately 1:4 in parts by weight.

2. Compositions of claim 1 in the form of capsules, externally coated with an acid-insoluble alkali-soluble coating.

3. Composition of claim 1 wherein the benzylacetamide is allylbenzylacetamide and the relaxant is 2,2-diisopropyl- 4-hydroxymethyl-1,3-dioxolane.

References Cited in the file of this patent Blicke: I. of the Am. Chem. Soc., vol. (1938), pp. 2924-2926.

Berger: Science, vol. 108, Nov. 19, 1948, pp. 561, 562.

Rice: I. of the Am. Pharm. Asso., Sci. Ed., vol. 33, September 1944, pp. 292, 293.

Nelson et al.: J. A. P. A., Sci. Ed., vol. 30, 1941, pp. -182.

Howard: Mod. Drug Encyclo., 5th ed., 1952, Drug PubL, N. Y. C., pp. 55, 341, 576, 1004-1005.

Tolagesic: Reg. T. M. No. 584,682, January 12, 1954. 

1. A COMPOSITION COMPRISING (1) HYPNOTIC BENZYLACETAMIDES OF THE FRMULA 